RESUMEN
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Piridazinas/farmacología , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/síntesis química , Sitios de Unión , Agonistas del GABA/administración & dosificación , Agonistas del GABA/síntesis química , Humanos , Ligandos , Estructura Molecular , Piridazinas/administración & dosificación , Piridazinas/síntesis química , Ratas , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Asunto(s)
Ansiolíticos/síntesis química , Agonistas de Receptores de GABA-A , Imidazoles/síntesis química , Triazinas/síntesis química , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Disponibilidad Biológica , Semivida , Humanos , Imidazoles/química , Imidazoles/farmacología , Técnicas de Placa-Clamp , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/fisiología , Saimiri , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacologíaRESUMEN
Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.
Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Agonistas de Receptores de GABA-A , Imidazoles/farmacología , Subunidades de Proteína/agonistas , Triazinas/farmacología , Administración Oral , Animales , Ataxia/tratamiento farmacológico , Sitios de Unión , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Femenino , Agonistas del GABA/farmacocinética , Agonistas del GABA/farmacología , Imidazoles/farmacocinética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Estructura Molecular , Subunidades de Proteína/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Saimiri , Relación Estructura-Actividad , Triazinas/farmacocinéticaRESUMEN
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.